Key Laboratory for Advanced Materials, School of Chemistry & Molecular Engineering, East China University of Science and Technology, Shanghai 200237, PR China.
Key Lab of Resource Chemistry of MOE & Shanghai Key Lab of Rare Earth Functional Materials, Shanghai Normal University, Shanghai 200234, PR China.
J Inorg Biochem. 2021 Mar;216:111354. doi: 10.1016/j.jinorgbio.2021.111354. Epub 2021 Jan 8.
Multifunctional drugs with synergistic effects have been widely developed to enhance the treatment efficiency of various diseases, such as malignant tumors. Herein, a novel bifunctional manganese(I)-based prodrug [MnBr(CO)(APIPB)] (APIPB = N-(2-aminophen-yl)-4-(1H-imidazo[4,5-f] [1, 10] phenanthrolin-2-yl)benzamide) with inhibitory histone deacetylase (HDAC) activity and light-controlled carbon monoxide (CO) delivery was successfully designed and synthesized. [MnBr(CO)(APIPB)] readily released CO under visible light irradiation (λ > 400 nm) through which the amount of released CO could be controlled by manipulating light power density and illumination time. In the absence of light irradiation, the cytotoxic effect of [MnBr(CO)(APIPB)] on cancer cells was greater than that of the commercially available HDAC inhibitor MS-275. Consequently, with a combination of CO delivery and HDAC inhibitory activity, [MnBr(CO)(APIPB)] showed a remarkably enhanced antitumor effect on HeLa cells (IC = 3.2 μM) under visible light irradiation. Therefore, this approach shows potential for the development of medicinal metal complexes for combined antitumor therapies.
多功能药物具有协同作用，已被广泛开发用于提高各种疾病（如恶性肿瘤）的治疗效率。在此，设计并合成了一种新型双功能锰（I）前药[MnBr(CO)(APIPB)]（APIPB=N-(2-氨基苯基)-4-(1H-咪唑并[4,5-f][1,10]菲咯啉-2-基)苯甲酰胺），具有抑制组蛋白去乙酰化酶（HDAC）活性和光控一氧化碳（CO）释放功能。[MnBr(CO)(APIPB)]在可见光照射（λ>400nm）下可迅速释放 CO，通过控制光功率密度和照射时间可以控制 CO 的释放量。在没有光照的情况下，[MnBr(CO)(APIPB)]对癌细胞的细胞毒性作用大于市售的 HDAC 抑制剂 MS-275。因此，通过 CO 释放和 HDAC 抑制活性的结合，[MnBr(CO)(APIPB)]在可见光照射下对 HeLa 细胞（IC=3.2μM）表现出显著增强的抗肿瘤作用。因此，这种方法为开发用于联合抗肿瘤治疗的药用金属配合物提供了潜力。
